Synapses are dynamically regulated on the milliseconds to minutes time scale. Although synaptic plasticity plays a crucial role throughout the brain, and dysfunction has been implicated in numerous neurological disorders, the many interacting forms of plasticity remain poorly understood. Our long-term goal is to determine the mechanisms and functional consequences of short-term plasticity. By studying multiple forms of plasticity at different synapses we will discern general features and synapse-specific specializations tailored to differing functional roles. We will focus on the hypothesis that specialized calcium sensors respond to presynaptic calcium signals to enhance neurotransmitter release. Our findings suggest that facilitation and posttetanic potentiation (PTP) use 2 different types of calcium sensors to enhance transmission on different time scales. Facilitation is a form of synaptic enhancement that lasts for hundreds of milliseconds. One proposed mechanism for facilitation is that a specialized calcium sensor transiently increases the probability of release, yet such a sensor has not been identified, and its very existence has been disputed. We will test the hypothesis that facilitation is mediated by synaptotagmin 7 (syt7), which is a calcium-sensitive isoform with slow kinetics. In preliminary studies we find tha in syt7 knockout mice, facilitation is eliminated even though the initial probability of release an presynaptic calcium signals are unaltered. Viral expression of syt7 restores facilitation in syt7 knockout animals. These studies indicate that we have identified the long sought after calcium sensor for facilitation. Future studies will clarify the role of syt7 in facilitation and other aspcts of synaptic signaling. PTP is a form of synaptic enhancement lasting for tens of seconds following a period of high-frequency firing of presynaptic neurons. The molecular basis of PTP is unclear. We have recently shown that PKC? is a calcium sensor for PTP at the calyx of Held. Our previous studies and preliminary findings indicate that calcium-dependent PKC isoforms have specialized roles in short-term plasticity at the calyx of Held. We will clarify the roles of different PKC isoforms and splice variants in PTP at the calyx of Held and determine if these results can be generalized to other synapses. We will also clarify the mechanism of PTP by determining the target(s) of PKC in PTP. We will test the hypothesis that PKC produces PTP by phosphorylating Munc18-1 by using a knockin mouse that we recently made in which we replace native Munc18-1 with mutated Munc18-1 that cannot be phosphorylated by PKC. Preliminary studies suggest that PKC phosphorylation of Munc18-1 contributes to PTP in specialized ways at different synapses. By revealing the mechanisms underlying facilitation and PTP, these studies could resolve longstanding debates about crucial forms of short-term plasticity, and enable future studies that may lead to a deeper understanding of the functional importance of facilitation and PTP.